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Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007–2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

Abstract Background Several studies have shown a high rate of consanguinity and endogamy in North African populations. As a result, the frequency of autosomal recessive diseases is relatively high in the region with the co‐occurrence of two or more diseases. Methods We report here on a consanguineous Libyan family whose child was initially diagnosed as presenting Fanconi anemia (FA) with uncommon skeletal deformities. The chromosome breakage test has been performed using mitomycin C (MMC) while molecular analysis was performed by a combined approach of linkage analysis and whole exome sequencing. Results Cytogenetic analyses showed that the karyotype of the female patient is 46,XY suggesting the diagnosis of a disorder of sex development (DSD). By looking at the genetic etiology of FA and DSD, we have identified p.[Arg798*];[Arg798*] mutation in FANCJ (OMIM #605882) gene responsible for FA and p.[Arg108*];[Arg1497Trp] in EFCAB6 (Gene #64800) gene responsible for DSD. In addition, we have incidentally discovered a novel mutation p.[Gly1372Arg];[Gly1372Arg] in the ERCC6 (CSB) (OMIM #609413) gene responsible for COFS that might explain the atypical severe skeletal deformities. Conclusion The co‐occurrence of clinical and overlapping genetic heterogeneous entities should be taken into consideration for better molecular and genetic counseling.